The body's defense system can be divided into two components, the innate and adaptive immune systems. The innate immune system acts as the first line of defense against invading pathogens (e.g., bacteria) and is found in plants and all animals. The response is very rapid, but often is unable to clear the infecting pathogen by itself, and therefore, it signals the adaptive immune system to help. The adaptive immune system is very specific and specialized at eliminating foreign pathogens from the body, but its response is slower and requires time to develop. Eventually, the invading pathogen is removed by the inflammatory response generated by the immune system. However, a prolonged and overactive inflammatory response can have detrimental effects on the body, as is seen in inflammatory bowel disease (IBD). The innate immune system detects foreign pathogens, such as bacteria, by recognizing components of the pathogen via receptors, termed toll-like receptors (TLRs). TLRs are located on the surface of specialized cells (dendritic cells and macrophages) and binding of the pathogenic component (agonist) causes them to become activated and release messenger molecules (called cytokines) that further stimulate the innate and adaptive immune systems. Additional components of the innate immune system are the epithelial cells that line the stomach and intestines. In addition to forming a physical barrier to pathogen invasion, epithelial cells also secrete small proteins, termed beta (2)-defensins, which are capable of killing bacteria. Recently, 2-defensins have been shown to activate dendritic cells and macrophages by a TLR-dependent mechanism and may represent a link between the innate and adaptive immune system. The goal of project outlined in the following proposal is to determine if 2-defensins play a critical role in the inflammatory response seen during gastrointestinal (GI) inflammation. Thus the project deals with the immune aspects and mechanism (i.e., pathogenesis) involved in the generation of GI inflammation. Although a great deal of research has been conducted in these areas, what initiates and causes the inflammatory response to persist has not been fully clarified. Evidence obtained from IBD patients demonstrate that defensins are significantly increased during active disease. Similar findings have been seen in mouse models of GI inflammation. We will employ experimental models of GI inflammation to characterize and determine the role of 2-defensins in the inflammatory mechanism mediating IBD. More specifically, we will (1) examine their ability to activate dendritic cells and macrophages by a TLR4-mediated pathway and promote an ensuing pro- inflammatory T cell (adaptive immune) response and (2) determine if animals lacking a specific 2-defensin, Defb1, are more or less susceptible to gastrointestinal inflammation. By evaluating the function of 2-defensins to activate immune cells, we will be able to further define the potential mechanism involved in the generation/perpetuation of chronic GI inflammatory disorders. By increasing our understanding of these mechanisms, a greater potential exists to develop new therapies to treat these disorders. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis affect greater than 1 million people in the United States alone. In recent years, it has become increasingly apparent that the innate immune system and its components play a critical role in chronic gastrointestinal (GI) inflammation;however, the exact nature of their involvement remains to be fully elucidated. The ultimate goal of the proposed project is to evaluate the role of beta-defensins (key components of the innate immune system) in the pathogenesis of chronic gastrointestinal inflammation. By increasing our understanding and knowledge of components involved in the pathogenic mechanism of GI Inflammation, a greater potential exists to develop new therapies and treat these disorders.